PROJECT SUMMARY - UNIVERSITY OF NORTH CAROLINA-CHAPEL HILL, FROHLICH The alpha oscillation is a thalamo-cortical rhythm (8-12 Hz) that serves important functional roles in cognition and behavior. Transcranial alternating current stimulation (tACS) has been shown to alter cortical alpha oscillations and associated cognitive function in healthy human participants. However, it remains unclear how tACS engages and modulates thalamo-cortical oscillations as a function of stimulation dose (frequency, amplitude, and duration). Bridging this gap will enable the development of tACS paradigms for targeting pathological changes in alpha oscillations in psychiatric illnesses such as depression, schizophrenia, and autism. The long-term goal of our research is to combine computational modeling, in vitro and in vivo animal experiments, and human studies to develop and validate tACS paradigms for the treatment of psychiatric disorders. The objective of this application is to (1) mechanistically dissect and optimize the modulation of thalamo-cortical network dynamics by tACS as a function of stimulation parameters, and (2) validate the target engagement by tACS in healthy control participants and patients. We will test the central hypothesis that tACS modulates alpha oscillations in the thalamo-cortical system as a function of the stimulation parameters frequency, amplitude, and duration. The rationale of this work is that mechanism-based dose optimization of tACS will increase its efficacy and thus provide new scientific and therapeutic opportunities. Based on comprehensive preliminary data, the three specific aims are: (1) to understand the role of tACS frequency and amplitude in modulating thalamo-cortical alpha oscillations, (2) to map and mechanistically dissect the outlasting effects as a function of tACS duration, and (3) to validate tACS for the modulation of alpha oscillations in human participants. The work is innovative in its interdisciplinary and translational design; the proposed research overcomes the limitations of individual methods by integrating in vivo and in vitro animal studies with computational modelling to optimize tACS for targeting thalamo-cortical alpha oscillations and validates these findings in human participants. This is a critical step forward from today?s approach to tACS, which does not consider how functional interaction with subcortical structures such as the thalamus shapes target engagement. The proposed research is significant since it provides mechanistic understanding how to optimize tACS to target alpha oscillations, which play a central role in both physiological and pathological states. Ultimately, this work will enable the rational choice of stimulation dose in the next generation of tACS studies, both for studying the functional role of thalamo-cortical oscillations in behavior and for treating psychiatric disorders.